Human Immunodeficiency Viruses (HIV) infect more than 40 million people worldwide. Effective antiretroviral therapy (ART) has fundamentally altered the course of HIV disease by reducing HIV replication and improving immune function. This has led to reductions in the incidence of many HIV-associated complications. Complications of the central nervous system (CNS) have persisted despite ART, particularly HIV-associated Neurocognitive Disorder (HAND). Immune recovery disease (IRD) may be the reason. IRD occurs when the restored immune system reacts to foreign and self-antigens and can result in substantial tissue injury and death. IRD can also cause less severe - but clinically significant - injury of several organs in the absence of opportunistic pathogens. The primary objective of this project will be to compare ART-induced immune recovery in cerebral-spinal fluid (CSF) and blood to changes in neuropsychological (NP) performance. We propose to accomplish this by studying 40 HIV-infected individuals before and after initiation of new ART regimens. Because the project will focus on the CNS complications of IRD, half the volunteers will have HAND before treatment and half will not. Study visits will include sampling of blood and CSF, standardized neuromedical and NP testing assessments, and a targeted panel of biomarkers. T-cell surface phenotypes, chemokine receptor expression, and functional response to HIV peptides will be characterized in blood-derived and CSF-derived cells. The overall hypothesis is that the impact of immune recovery on the CNS will differ between HIV-infected individuals who have HAND and those who do not. In particular, we expect that HAND will be associated with greater homing of activated CD4+ T-cells and CD8+ effector memory T-cells into the CNS and that, within the HAND group, homing of these cells will be associated with less improvement or worsening of NP performance. The data generated by this project will have important implications for the pathogenesis of HIV in the brain and will support the longer term objective of this and future projects, to identify the predictors and treatment of IRD of the CNS. The proposed project will have substantial synergy with an existing NIMH-funded project at the University of California, San Diego (UCSD). PUBLIC HEALTH RELEVANCE: Immune-mediated brain injury has substantial public health relevance. Understanding mild and moderate IRD will also improve understanding of the pathogenesis of the neurological complications of HIV and other neuroinflammatory disorders. This knowledge may improve management of HAND in the U.S. and in more resource-limited settings, such as sub-Saharan Africa. This knowledge will have direct relevance for an important and still controversial question in the HIV/AIDS field, the optimal time to initiate therapy.